Redox-dependent gating of VDAC by mitoNEET.

MitoNEET is an outer mitochondrial membrane protein essential for sensing and regulation of iron and reactive oxygen species (ROS) homeostasis. It is a key player in multiple human maladies including diabetes, cancer, neurodegeneration, and Parkinson's diseases. In healthy cells, mitoNEET receives its clusters from the mitochondrion and transfers them to acceptor proteins in a process that could be altered by drugs or during illness. Here, we report that mitoNEET regulates the outer-mitochondrial membrane (OMM) protein voltage-dependent anion channel 1 (VDAC1). VDAC1 is a crucial player in the cross talk between the mitochondria and the cytosol. VDAC proteins function to regulate metabolites, ions, ROS, and fatty acid transport, as well as function as a "governator" sentry for the transport of metabolites and ions between the cytosol and the mitochondria. We find that the redox-sensitive [2Fe-2S] cluster protein mitoNEET gates VDAC1 when mitoNEET is oxidized. Addition of the VDAC inhibitor 4,4'-diisothiocyanatostilbene-2,2'-disulfonate (DIDS) prevents both mitoNEET binding in vitro and mitoNEET-dependent mitochondrial iron accumulation in situ. We find that the DIDS inhibitor does not alter the redox state of MitoNEET. Taken together, our data indicate that mitoNEET regulates VDAC in a redox-dependent manner in cells, closing the pore and likely disrupting VDAC's flow of metabolites

Multi-factor, multi-state, multi-model scenarios: Exploring food and climate futures for Southeast Asia

Decision-makers aiming to improve food security, livelihoods and resilience are faced with an uncertain future. To develop robust policies they need tools to explore the potential effects of uncertain climatic, socioeconomic, and environmental changes. Methods have been developed to use scenarios to present alternative futures to inform policy. Nevertheless, many of these can limit the possibility space with which decision-makers engage. This paper will present a participatory scenario process that maintains a large possibility space through the use of multiple factors and factor-states and a multi-model ensemble to create and quantify four regional scenarios for Southeast Asia. To do this we will explain 1) the process of multi-factor, multi-state building was done in a stakeholder workshop in Vietnam, 2) the scenario quantification and model results from GLOBIOM and IMPACT, two economic models, and 3) how the scenarios have already been applied to diverse policy processes in Cambodia, Laos, and Vietnam

Prospective open-label study of add-on and monotherapy topiramate in civilians with chronic nonhallucinatory posttraumatic stress disorder

BACKGROUND: In order to confirm therapeutic effects of topiramate on posttraumatic stress disorder (PTSD) observed in a prior study, a new prospective, open-label study was conducted to examine acute responses in chronic, nonhallucinatory PTSD. METHODS: Thirty-three consecutive newly recruited civilian adult outpatients (mean age 46 years, 85% female) with DSM-IV-diagnosed chronic PTSD, excluding those with concurrent auditory or visual hallucinations, received topiramate either as monotherapy (n = 5) or augmentation (n = 28). The primary measure was a change in the PTSD Checklist-Civilian Version (PCL-C) score from baseline to 4 weeks, with response defined as a ≥ 30% reduction of PTSD symptoms. RESULTS: For those taking the PCL-C at both baseline and week 4 (n = 30), total symptoms declined by 49% at week 4 (paired t-test, P < 0.001) with similar subscale reductions for reexperiencing, avoidance/numbing, and hyperarousal symptoms. The response rate at week 4 was 77%. Age, sex, bipolar comorbidity, age at onset of PTSD, duration of symptoms, severity of baseline PCL-C score, and monotherapy versus add-on medication administration did not predict reduction in PTSD symptoms. Median time to full response was 9 days and median dosage was 50 mg/day. CONCLUSIONS: Promising open-label findings in a new sample converge with findings of a previous study. The use of topiramate for treatment of chronic PTSD, at least in civilians, warrants controlled clinical trials

A randomized, double-blind, placebo-controlled trial to assess the efficacy of topiramate in the treatment of post-traumatic stress disorder

<p>Abstract</p> <p>Background</p> <p>Topiramate might be effective in the treatment of posttraumatic stress disorder (PTSD) because of its antikindling effect and its action in both inhibitory and excitatory neurotransmitters. Open-label studies and few controlled trials have suggested that this anticonvulsant may have therapeutic potential in PTSD. This 12-week randomized, double-blind, placebo-controlled clinical trial will compare the efficacy of topiramate with placebo and study the tolerability of topiramate in the treatment of PTSD.</p> <p>Methods and design</p> <p>Seventy-two adult outpatients with DSM-IV-diagnosed PTSD will be recruited from the violence program of Federal University of São Paulo Hospital (UNIFESP). After informed consent, screening, and a one week period of wash out, subjects will be randomized to either placebo or topiramate for 12 weeks. The primary efficacy endpoint will be the change in the Clinician-administered PTSD scale (CAPS) total score from baseline to the final visit at 12 weeks.</p> <p>Discussion</p> <p>The development of treatments for PTSD is challenging due to the complexity of the symptoms and psychiatric comorbidities. The selective serotonin reuptake inhibitors (SSRIs) are the mainstream treatment for PTSD, but many patients do not have a satisfactory response to antidepressants. Although there are limited clinical studies available to assess the efficacy of topiramate for PTSD, the findings of prior trials suggest this anticonvulsant may be promising in the management of these patients.</p> <p>Trial Registration</p> <p>NCT 00725920</p

Forgotten Sources of Capital for the Family-Owned Business

The recent scandals on Wall Street in the banking and savings and loan industries have created a financial crisis for many family businesses, particularly those in smaller towns and cities. The long-standing personal relationships with financial intermediaries have been altered by the loss of these financial organizations and by heightened government intervention and regulation. To manage the finances of a family business successfully, the owners must reassess forgotten sources of capital for their businesses. This article examines these sources of capital for family businesses in the United States.Yeshttps://us.sagepub.com/en-us/nam/manuscript-submission-guideline

Towards Understanding the Origin of Cosmic-Ray Electrons

Precision results on cosmic-ray electrons are presented in the energy range from 0.5 GeV to 1.4 TeV based on 28.1 x 10(6) electrons collected by the Alpha Magnetic Spectrometer on the International Space Station. In the entire energy range the electron and positron spectra have distinctly different magnitudes and energy dependences. The electron flux exhibits a significant excess starting from 42.1(-5.2)(+5.4) GeV compared to the lower energy trends, but the nature of this excess is different from the positron flux excess above 25.2 +/- 1.8 GeV. Contrary to the positron flux, which has an exponential energy cutoff of 810(-180)(+310) GeV, at the 5 sigma level the electron flux does not have an energy cutoff below 1.9 TeV. In the entire energy range the electron flux is well described by the sum of two power law components. The different behavior of the cosmic-ray electrons and positrons measured by the Alpha Magnetic Spectrometer is clear evidence that most high energy electrons originate from different sources than high energy positrons